EP3059238B1 - Composé hétérocyclique condensé, son procédé de préparation, composition pharmaceutique et leurs utilisations - Google Patents

Composé hétérocyclique condensé, son procédé de préparation, composition pharmaceutique et leurs utilisations Download PDF

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EP3059238B1
EP3059238B1 EP14853907.5A EP14853907A EP3059238B1 EP 3059238 B1 EP3059238 B1 EP 3059238B1 EP 14853907 A EP14853907 A EP 14853907A EP 3059238 B1 EP3059238 B1 EP 3059238B1
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compound
synthesis
ring
alkyl
group
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EP3059238A1 (fr
EP3059238A4 (fr
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Zusheng XU
Yangtong Lou
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Shanghai Yingli Pharm Co Ltd
Shanghai Yingli Pharmaceutical Co Ltd
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Shanghai Yingli Pharm Co Ltd
Shanghai Yingli Pharmaceutical Co Ltd
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention especially relates to a fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof.
  • Phosphatidylinositol 3-kinase is a type of intracellular phosphatidylinositol kinase that can catalyze the phosphorylation of the 3-hydroxy of phosphatidylinositol.
  • the PI3K can be divided into type I kinase, type II kinase, and type III kinase, and the most extensively investigated one is the type I PI3Ks that can be activated by cell surface receptors.
  • Type I PI3Ks in mammalian cells are further divided into two groups based on their structures and receptors, class Ia and class Ib, which transmits signals from tyrosine kinase-coupled receptors and G protein-coupled receptors, respectively.
  • Class Ia PI3Ks include PI3K ⁇ , PI3K ⁇ and PI3K ⁇
  • class Ib PI3Ks include PI3K ⁇ ( Trends Biochem. Sci., 1997, 22, 267-272 ).
  • Class Ia PI3Ks are dimers of a catalytic subunit, p110, and a regulatory subunit, p85, having dual activity of lipid kinases and protein kinases ( Nat.Rev.Cancer 2002, 2, 489-501 ), which are considered to be related to the cell proliferation, developing of cancers, immunological diseases and inflammation-relating diseases.
  • PI3K inhibitors such as: WO2008064093 , WO2007044729 , WO2008127594 , WO2007127183 , WO2007129161 , US20040266780 , WO2007072163 , WO2009147187 , WO2009147190 , WO2010120987 , WO2010120994 , WO2010091808 , WO2011101429 , WO2011041399 , WO2012040634 , WO2012037226 , WO2012032065 , WO2012007493 , WO2012135160 , US2012208808 , US2010298319 , US2013123255 , WO2010114484 , US2010069629 , WO2010114494 , US2010324284 , US2013072481 , US2011009403 , US2011130395 .
  • the problem to be solved by the present invention is to provide a fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof which is totally different from the prior art.
  • the fused heterocyclic compound of the invention as an inhibitor with selectivity against PI3K ⁇ can be used to prepare a medicament for treating cancers, infection, inflammation or cell proliferation diseases such as autoimmune diseases.
  • R 2 is preferably -(CR 8 R 9 ) m NR 5 R 6 or -O(CR 8 R 9 ) m NR 5 R 6 ;
  • R 3 is preferably a hydrogen, a deuterium, a halogen or a C 1-3 alkyl;
  • A is preferably CR 4a ;
  • R 4a is preferably a hydrogen, a halogen or a C 1-3 alkyl;
  • E is preferably CR 4e ;
  • R 4e is preferably a hydrogen, a C 1-3 alkoxy or -NR 5 R 6 ;
  • J is preferably CR 4j ;
  • R 4j is preferably a hydrogen, a halogen or a C 1-3 alkyl;
  • ring Q is a benzene;
  • (R 1 ) k1 represents that the hydrogens to which attached to the ring Q are substituted by 0-k1 occurrences of R 1 , at each occurrence the R 1 is the same
  • R 8 is preferably a hydrogen, a deuterium, a halogen or a C 1-3 alkyl;
  • (CR 8 R 9 ) m represents that 0 to m (CR 8 R 9 ) are linked, R 8 and R 9 are the substituents attached to the formed carbon chain, wherein each R 8 and R 9 are the same or different from each other, and are each preferably independently a hydrogen, a deuterium, a halogen or a C 1-3 alkyl;
  • m, k or k1 is preferably independently 0 or 1.
  • a 1 and A 2 are N at the same time; more preferably, R 2 is or; more preferably, R 3 is a hydrogen; more preferably, A is CR 4a ; R 4a is more preferably a hydrogen; more preferably, E is CR 4e ; R 4e is more preferably a hydrogen, a methoxy or -NH 2 ; more preferably, G is CR 4g ; R 4g is more preferably more preferably, J is CR 4j ; R 4j is more preferably a hydrogen; Ring Q is a benzene; (R 1 ) k1 represents that the hydrogens attached to the ring Q are substituted by 0-k1 occurrences of R 1 , at each occurrence the R 1 is the same or different from each other, and is each more preferably independently fluorine; more preferably, m, k or k1 is independently 0 or 1.
  • the formula I is preferably a compound selected from the group consisting of:
  • the present invention also provides a compound represented by the structure selected from the group consisting of 1-a, 7-a and 28-b as set out below:
  • At least one of the fused heterocyclic compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph thereof prepared by the above routes can be purified by column chromatograph, HPLC, crystallization or other proper conditions.
  • the conditions and steps used in the purification method such as column chromatograph, HPLC and crystallization can refer to conventional conditions and steps in the art.
  • the above fused heterocyclic compound provided in the present invention can exhibit tautomerism, structural isomerism and stereoisomerism.
  • the present invention includes any tautomer, structural isomer or stereo isomer of the compound and their mixtures, they have the ability of regulating the activity of the kinase and this ability is not limited to any isomer or the form of its mixture.
  • the present disclosure also describes a use of the fused heterocyclic compound represented by formula I, formula II or formula III, pharmaceutically acceptable salt, hydrate, solvate, polymorph thereof in manufacturing an inhibitor of kinase.
  • the present disclosure also describes a use of the fused heterocyclic compound represented by formula I, formula II or formula III, pharmaceutically acceptable salt, hydrate, solvate, polymorph thereof in manufacturing a medicament for treating and/or preventing a disease related to the kinase.
  • the kinase is preferably PI3 kinase (PI3K), more preferably p110 ⁇ subtype of PI3K (PI3K).
  • the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective dosage of one or more of the fused heterocyclic compounds represented by formula I, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.
  • the term "therapeutically effective dosage” means (i) the amount of the compound of the present invention required for preventing or treating the specific disease or disorder described in the application; (ii) the amount of the compound of the present invention required for attenuating, ameliorating or eliminating one or more symptoms of the specific disease or disorder described in the application; or (iii) the amount of the compound of the present invention required for preventing or delaying the onset of one or more symptoms of the specific disease or disorder described in the application.
  • the dosage for treating human patients may range from 0.0001 mg/kg to 50 mg/kg, most typically 0.001 mg/kg to 10 mg/kg body weight, e.g. within the range from 0.01 mg/kg to 1 mg/kg. Such a dosage may be administered, for example 1-5 times a day.
  • the pharmaceutical composition can be prepared into a variety of unit dose formulations, such as tablets, pills, powder, liquid, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions) and preferably liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions).
  • any known and widely used excipient in the art can be used.
  • carriers such as lactose, sugar, sodium chloride, glucose, carbamide, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid
  • adhesive such as water, ethanol, propanol, ordinary syrup, glucose solution, starch solution, gelatin solution , carboxymethyl cellulose, lac, methyl cellulose and potassium phosphate, Polyvinylpyrrolidone
  • disintegrant such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, the polyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, stearic acid monoglyceride, starch and lactose
  • disintegration inhibitor such as sugar, glyceryl tristearate, coconut oil and hydrogenated oil
  • adsorption accelerant such as quaternary amine base and sodium dodecyl
  • any known and widely used excipient in the art can be used, for example, carriers (such as lactose, starch, coconut oil, hydrogenated vegetable oil, kaolin and talc powder), adhesive (such as acacia powder, tragacanth gum powder, gelatin and ethanol), disintegrant (such as agar and kelp powder).
  • carriers such as lactose, starch, coconut oil, hydrogenated vegetable oil, kaolin and talc powder
  • adhesive such as acacia powder, tragacanth gum powder, gelatin and ethanol
  • disintegrant such as agar and kelp powder.
  • any known and widely used excipient in the art can be used, for example, polyethyleneglycol, coconut oil, higher alcohols, higher alcohol esters, gelatin and semisynthetic glyceride.
  • the solution or suspension (preferably adding a proper amount of sodium chloride, glucose or glycerin) can be sterilized, and then with which prepare the injection preparation having isosmotic pressure with the blood.
  • any commonly used carriers in the art can also be used.
  • water, ethanol, propanediol, ethoxylated isostearyl alcohol, polyoxy isostearyl alcohol and the polyethylene sorbitan fatty acid ester for instance, water, ethanol, propanediol, ethoxylated isostearyl alcohol, polyoxy isostearyl alcohol and the polyethylene sorbitan fatty acid ester.
  • conventional solvents, buffer and analgetic can also be added.
  • the administration of the pharmaceutical composition do not have special requirements.
  • Various preparation for administration is selected according to the age, gender, other condition and symptoms of patients. For instance, tablets, pills, solutions, suspensions, emulsions, granules or capsules for oral administration; injection preparations can be administered individually, or mixed with an injectable conveying liquid (such as glucose solution and amino acid solution) and transvenously injected; the suppository is administered rectally.
  • an injectable conveying liquid such as glucose solution and amino acid solution
  • the present disclosure also describes a use of the pharmaceutical composition in manufacturing a kinase inhibitor.
  • the present disclosure also describes a use of the pharmaceutical composition in manufacturing a medicament for treating and/or preventing a disease related to kinase.
  • the kinase is preferably PI3 kinase.
  • the "disease related to kinase” includes, but is not limited to, the disease selected from the group consisting of cancer, immunological diseases, metabolic and/or endocrine dysfunction, angiocardiopathy, virus infections and inflammation, and nerve diseases, preferably cancer and/or immunological diseases.
  • the immunological diseases include but are not limited to the disease selected from the group consisting of rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn disease and systemic lupus erythematosus.
  • the angiocardiopathy includes but is not limited to neoplastic hematologic disorder.
  • the virus infections and inflammation include but are not limited to asthma and/or atopic dermatitis.
  • alkyl refers to a saturated linear or branched-chain aliphatic hydrocarbyl containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and the various isomers thereof; as well as the alkyl groups containing 1 to 4 substituents selected from the group consisting of: a deuterium, a halogen
  • alkylene refers to a subsaturated linear or branched-chain aliphatic hydrocarbyl containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, such as a methylene, an ethylene, a n -propylene, an isopropylene, a n-butylene, a tert- butylene, an isobutylene, a pentylene, a hexylene, a heptylene, an octylene, a nonylene, a decylene, 4,4-dimethylpentylene, 2,2,4-trimethylpentylene, an undecylene, a dodecylene, and the various isomers thereof; as well as the alkylene containing 1 to 4 substituents selected from the group consisting of: a deuterium, a hal
  • alicyclic ring includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl or tricyclic alkyl exhibited in the form of a fused ring or a bridge ring containing 3 to 20 ring-forming carbon atoms, preferably 3 to 12 carbon atoms, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl; the cycloalkyl may be optionally substituted by 1 to 4 substituents selected from the group consisting of: a deuterium, a halogen, an alkyl, an alkoxy,
  • any cycloalkyl ring may be fused to a cycloalkyl, an aryl, a heteroaryl or a heterocycloalkyl ring to form a fused ring, a bridge ring or a spiro ring.
  • alkoxy refers to a cyclic or non-cyclic alkyl group containing the indicated number of carbon atoms and having a connection through an oxygen bridge.
  • alkoxy includes the definitions of "alkyl” and “cycloalkyl” mentioned above.
  • alkenyl refers to a straight-chain, branched-chain or cyclic non-aromatic hydrocarbyl having the indicated number of carbon atoms and at least one carbon-carbon double bond. Preferably, there is one carbon-carbon double bond, and may have up to four non-aromatic carbon-carbon double bonds.
  • C 2 -C 12 alkenyl refers to an alkenyl group having 2 to 12 carbon atoms.
  • C 2 -C 6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, including vinyl, propenyl, butenyl, 2-methyl-butenyl and cyclohexenyl.
  • a double bond may locate at the straight-chain, branched or cyclic portion of the alkenyl group and, where specified, the alkenyl group may be substituted.
  • alkynyl refers to a straight-chain, branched-chain or cyclic hydrocarbyl having the indicated number of carbon atoms and at least one carbon-carbon triple bond. It may have up to three carbon-carbon triple bonds.
  • C 2 -C 12 alkynyl refers to an alkynyl group having 2 to 12 carbon atoms.
  • C 2 -C 6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, including an ethynyl, a propynyl, a butynyl and 3-methyl-1-butynyl.
  • aryl refers to any stable monocyclic or bicyclic carbocyclic ring containing up to 7 atoms in each ring, wherein at least one ring is an aromatic ring.
  • aryl group include phenyl, naphthyl, tetrahydronaphthyl, 2,3-indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. It can be understood that if an aryl substituent is a bicyclic ring having one non-aromatic ring, then the connection is through the aromatic ring.
  • aryl optionally substituted by the substituents selected from the group consisting of: a deuterium, a halogen (F, Br, Cl or I), an alkyl, an alkoxy, an aryl, an aryloxy, an aryl or a diaryl substituted by an aryl, an arylalkyl, an arylalkoxy, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a cycloalkylalkyl, a cycloalkylalkoxy, optionally substituted amino, a hydroxyl, a hydroxylalkyl, an acyl, an aldehyde group, a heteroaryl, a heteroaryloxy, a heterocycloalkyl, a heterocycloalkyloxy, an arylheteroaryl, an arylalkoxycarbonyl, a heteroarylalkyl, a heteroaryl
  • alkylthio refers to a cyclic or non-cyclic alkyl group containing the indicated number of carbon atoms and having a connection through a sulfur atom. Thus, “alkylthio” includes the definition of “alkyl” and “cycloalkyl”.
  • halogen refers to fluorine, chlorine, bromine, iodine, or astatine.
  • haloalkyl refers to an alkyl group substituted by halogen at optionally position.
  • haloalkyl includes the definition of "halogen” and “alkyl”.
  • haloalkoxy refers to an alkoxy group substituted by halogen at optionally position.
  • haloalkoxy includes the definition of "halogen” and "alkoxy”.
  • aryloxy refers to an aryl group containing the indicated number of carbon atoms and having a connection through an oxygen bridge. Thus, “aryloxy” includes the definition of "aryl”.
  • arylhetero or “heteroaryl” refers to any stable monocyclic or bicyclic ring containing up to 7 atoms in each ring, wherein at least one ring is an aromatic ring containing 1 to 4 heteroatoms selected from the group consisting of O, N, and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, imidazolyl, indolyl, indazolyl, triazolyl, tetrazolyl, benzotriazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, guanine group, furyl, thienyl, thiazolyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl.
  • heteroaryl should also be understood to include the N-oxide derivative of any nitrogen-containing heteroaromatic group. It can be understood that if a heteroaryl substituent is a bicyclic ring having one non-aromatic ring or one ring without heteroatom, then the connection is through the aromatic ring or the heteroatom contained in the ring.
  • Heteroaryl groups are optionally substituted by 1 to 4 substituents selected from the group consisting of a deuterium, a halogen, an alkyl, an alkoxy, a hydroxyl, an aryl, an aryloxy, an arylalkyl, a cycloalkyl, an alkylamino, an acylamino, an acyl, an arylcarbonylamino, an amino, a nitro, a cyano, a thiol and/or an alkylthio and/or any alkyl substituents.
  • substituents selected from the group consisting of a deuterium, a halogen, an alkyl, an alkoxy, a hydroxyl, an aryl, an aryloxy, an arylalkyl, a cycloalkyl, an alkylamino, an acylamino, an acyl, an arylcarbonylamino, an amino, a nitro
  • heterocyclic ring or “heterocyclic group” refers to 5 to 10 membered aromatic or non-aromatic heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting of O, N, and S, and bicyclic groups are also included. Therefore, the “heterocyclic group” includes the above heteroaryl groups, as well as their dihydro or tetrahydro analogs.
  • heterocyclic group examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, carbazyl, carbolinyl, cinnolinyl, furyl, imidazolyl, dihydroindolyl, indolyl, indazolyl, isobenzofuranyl, pseudoindolyl, isoquinoline, isothiazolyl, isoxazolyl, naphthalene pyrimidinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridazinyl, pyridazinyl
  • a heterocyclic group can be linked with other groups through a carbon atom or a heteroatom.
  • the C 2-20 heterocyclic group is preferably a C 2-8 saturated heterocyclic group, further preferably a C 4-5 saturated heterocyclic group, wherein the heteroatom is N, O or S, more preferably a C 4-5 saturated heterocyclic group containing two heteroatoms, such as piperazinyl or piperidyl.
  • the C 2-20 heterocyclic group has one heteroatom, the substituted position of which is preferably on a carbon atom or a heteroatom; where the C 2-20 heterocyclic group has two or more heteroatoms, the substituted position of which is preferably on the heteroatom.
  • heteroalicyclic ring or “heterocycloalkyl” used herein alone or as a part of other groups refers to a 4 to 12 membered saturated or partially unsaturated ring containing 1 to 4 heteroatoms (such as nitrogen, oxygen and/or sulphur).
  • the heterocycloalkyl groups may include at least one substituents, such as alkyl, halogen, oxo and/or any alkyl substituents set out above.
  • any heterocycloalkyl rings can be fused to a cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring, thereby to form a fused ring, a bridge ring or a spiro ring.
  • a heterocycloalkyl substituent can be linked with other groups through a carbon atom or a heteroatom therein.
  • the materials and reagents used in the present invention are all commercially available.
  • the room temperature in the present application refers to an environmental temperature which ranges from 10°C to 35°C.
  • the fused heterocyclic compound represented by formula I, II or III as described herein is an efficient PI3 kinase (especially PI3K ⁇ -selective) inhibitor which can be used for manufacturing a medicament for preventing and/or treating cell proliferation diseases such as cancer, infections, inflammation and autoimmune diseases.
  • Examples 4-6 and 11-22 are reference examples and are not according to the invention.
  • a mixture of compound 1-d (prepared according to the method disclosed in Heterocycles, 2012 , pages 1417 - 1426 ) (480 mg, 2.068 mmol), compound 1-e (prepared according to the method disclosed in WO 2009/147187 A1 ) (510 mg, 2.068 mmol), Pd 2 (dba) 3 (42 mg, 0.046 mmol), [(t-Bu) 3 PH]BF 4 (60 mg, 0.207 mmol), patassium flouride (470 mg, 8.276 mmol), tetrahydrofuran (15 mL) and water (1.5 mL) was heated to 50°C under nitrogen gas atomsphere and stirred for 7 hours.
  • compound 24-b was used to give compound 24-a (850 mg, 73%).
  • the isomers were characterized by 1H-NMR.
  • Table 1 shows the IC 50 values against PI3K ⁇ of the compounds in the present invention and the ratio of IC 50 values aganist PI3K ⁇ to PI3K ⁇ (referred to as ⁇ / ⁇ ).
  • Table 2 shows the ratio of IC 50 values against PI3K ⁇ to PI3K ⁇ of partial compounds (referred to as ⁇ / ⁇ ) and the ratio of IC 50 values against PI3K ⁇ to PI3K ⁇ (referred to as ⁇ / ⁇ ).
  • the compounds of the present invention have an excellent selective inhibition against PI3K ⁇ and are a type of selective inhibitor which possesses stronger inhibitory activity aganist PI3K ⁇ than that against PI3K ⁇ , PI3K ⁇ or PI3K ⁇ and can be an excellent immunosuppressant, and can be an agent useful for treating or preventing rejection responses in a variety of organ transplantation, allergic diseases (such as asthma and atopic dermatitis), autoimmune diseases (rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus), and neoplastic hematologic disorder and so on.
  • allergic diseases such as asthma and atopic dermatitis
  • autoimmune diseases rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus
  • neoplastic hematologic disorder and so on.

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Claims (9)

  1. Composé hétérocyclique condensé représenté par la formule I, sel, hydrate, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci,
    Figure imgb0122
     dans laquelle
    A1 est N ;
    A2 est N ;
    R2 est -(CR8R9)mNR5R6, -(CR8R9)mNR7C(=Y)R5, -(CR8R9)mNR7S(O)2R5, -(CR8R9)mOR5, -(CR8R9)mS(O)2R5, -(CR8R9)mS(O)2NR5R6, -C(OR5)R6R8, -C(=Y)R5, -C(=Y)OR5, -C(=Y)NR5R6, -C(=Y)NR7OR5, -C(=O)NR7S(O)2R5, -C(=O)NR7(CR8R9)mNR5R6, -NR7C(=Y)R6, -NR7C(=Y)OR6, -NR7C(=Y)NR5R6, -NR7S(O)2R5, -NR7S(O)2NR5R6, -SR5, -S(O)2R5, -S(O)2NR5R6, -SC(=Y)R5, -SC(=Y)OR5, -O(CR8R9)mNR5R6, un alkyle en C1 à C12, un alcényle en C2 à C8, un alcynyle en C2 à C8, un groupe carbocyclique en C3 à C12, un groupe hétérocyclique en C2 à C20, un aryle en C6 à C20 ou un hétéroaryle en C1 à C20 ;
    ou R2 possède une structure sélectionnée dans le groupe constitué de
    Figure imgb0123
    Figure imgb0124
    Figure imgb0125
     (R3)k indique que les hydrogènes liés au cycle morpholine sont remplacés par 0 à k occurrences de R3, à chaque occurrence, les R3 sont identiques les uns aux autres ou différents les uns des autres, et sont indépendamment un hydrogène, un deutérium, un halogène, un alkyle en C1 à C6, ou deux R3 quelconques sont liés par une liaison simple, un alkylène en C1 à C6 ou un alkylène en C1 à C6 substitué avec un ou deux hétéroatomes pour former une structure cyclique, l'hétéroatome est O, N ou S ;
    A est N ou CR4a ;
    D est N ;
    E est N ou CR4e ;
    G est CR4g ; R4g est -NR7S(O)2R5 ;
    J est N ou CR4j ;
    R4a, R4e et R4j sont chacun indépendamment un hydrogène, un halogène, -CN, un alkyle, un alcoxy, un alcényle, un alcynyle, un cycloalkyle, un hétérocycloalkyle, -NR5R6, -OR5, -SR5, -C(O)R5, -NR5C(O)R6, -N(C(O)R6)2, -NR5C(O)NR5'R6, -NR7S(O)2R5, -C(=O)OR5 ou -C(=O)NR5R6 ;
    le cycle Q est un benzène ;
    à chaque occurrence, les R1 sont identiques les uns aux autres ou différents les uns des autres, et sont chacun indépendamment un halogène, -CN, un alkyle, un alcoxy, un alcényle, un alcynyle, un cycloalkyle, un hétérocycloalkyle, -NR5R6, -OR5, -SR5, -C(O)R5, -NR5C(O)R6, -N(C(O)R6)2, -NR5C(O)NR5'R6, -NR7S(O)2R5, -C(=O)OR5 ou -C(=O)NR5R6 ;
    R5, R5', R6, R7 et R7' sont chacun indépendamment un hydrogène, un alkyle en C1 à C12, -(CH2)2-3NH2, un alcényle en C2 à C8, un alcynyle en C2 à C8, un groupe carbocyclique en C3 à C12, un groupe hétérocyclique en C2 à C20, un aryle en C6 à C20 ou un hétéroaryle en C1 à C20, ou R5, R6 conjointement avec les atomes d'azote ou de carbone auxquels ils sont directement liés forment un cycle hétérocyclique ou un cycloalkyle ; ou R7, R7' conjointement avec l'atome d'azote auquel R7 est directement lié forment un cycle hétérocyclique ; le cycle hétérocyclique ou le cycloalkyle est facultativement substitué avec le substituant sélectionné dans le groupe constitué d'un oxo, de -(CH2)mOR7, de -NR7R7', de -CF3, d'un halogène, de -SO2R7, de -C(=O)R7, de -NR7C(=Y)R7', de -NR7S(O)2R7', de -C(=Y)NR7R7', d'un alkyle en C1 à C12, d'un alcényle en C2 à C8, d'un alcynyle en C2 à C8, d'un groupe carbocyclique en C3 à C12, d'un groupe hétérocyclique en C2 à C20, d'un aryle en C6 à C20 ou d'un hétéroaryle en C1 à C20 ;
    (CR8R9)m indique que 0 à m (CR8R9) sont liés les uns aux autres, R8 et R9 sont les substituants liés à la chaîne carbonée formée, dans lequel les R8 et R9 sont identiques les uns aux autres ou différents les uns des autres, et sont chacun indépendamment un hydrogène, un deutérium, un halogène, -CN, un hydroxyle, un alcoxy, un alkyle en C1 à C12, un alcényle en C2 à C12, un alcynyle en C2 à C12, un cycloalkyle en C3 à C12, un aryle en C6 à C12, un hétérocycloalkyle de 3 à 12 chaînons ou un hétéroaryle de 5 à 12 chaînons ; ou R8, R9 conjointement avec les atomes auxquels ils sont liés forment un cycle carboné en C3 à C12 saturé ou partiellement insaturé ou un cycle hétérocyclique en C2 à C20 saturé ou partiellement insaturé ;
    où l'alkyle, le cycle carbocyclique et le cycle hétérocyclique peuvent être facultativement substitués avec le substituant sélectionné dans le groupe constitué d'un halogène, d'un hydroxyle, de -CN, de -CF3, de -NO2, d'un oxo, de -(CR8R9)mOR5 et d'un groupe hétérocyclique en C2 à C20 ;
    Y est O, S ou NR7 ;
    m, k ou k1 sont indépendamment 0, 1, 2, 3, 4, 5 ou 6.
  2. Composé hétérocyclique condensé, sel, hydrate, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci tel que défini dans la revendication 1, dans lequel
    R2 est -(CR8R9)mNR5R6 ou -O(CR8R9)mNR5R6 ;
    R3 est un hydrogène, un deutérium, un halogène ou un alkyle en C1 à C3 ;
    A est CR4a ; R4a est un hydrogène, un halogène ou un alkyle en C1 à C3 ;
    E est CR4e ; R4e est un hydrogène, un alcoxy en C1 à C3 ou -NR5R6 ;
    J est CR4j ; R4j est un hydrogène, un halogène ou un alkyle en C1 à C3 ;
    le cycle Q est un benzène ;
    R1 est un halogène ;
    R5, R6 et R7 sont chacun indépendamment un hydrogène, -(CH2)2-3NH2 ou un alkyle en C1 à C6, ou R5, R6 conjointement avec les atomes d'azote ou de carbone auxquels ils sont directement liés forment un cycle hétérocyclique ou un cycloalkyle, le cycle hétérocyclique ou le cycloalkyle est facultativement substitué avec le substituant sélectionné dans le groupe constitué de -(CH2)mOR7, -SO2R7, -C(=O)R7, un alkyle en C1 à C3, un groupe carbocyclique en C3 à C6 et un groupe hétérocyclique en C2 à C5 ; dans lequel le cycle hétérocyclique est un cycle hétéroalicyclique de 4 à 6 chaînons contenant de l'azote ou contenant de l'oxygène, le cycloalkyle est un cycloalkyle de 4 à 6 chaînons ;
    R8 et R9 sont chacun indépendamment un hydrogène, un deutérium, un halogène ou un alkyle en C1 à C3 ;
    m, k ou k1 sont indépendamment 0 ou 1.
  3. Composé hétérocyclique condensé, sel, hydrate, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci tel que défini dans la revendication 1, dans lequel,
    R2 possède une structure sélectionnée dans le groupe constitué de
    Figure imgb0126
    Figure imgb0127
    Figure imgb0128
    Figure imgb0129
     et
    Figure imgb0130
     R3 est un hydrogène ;
    A est CR4a ; R4a est un hydrogène ;
    E est CR4e ; R4e est un hydrogène, un méthoxy ou -NH2 ;
    G est CR4g ; R4g est
    Figure imgb0131
     J est CR4j ; R4j est un hydrogène ;
    le cycle Q est un benzène ;
    R1 est un fluor ;
    m, k ou k1 est indépendamment 0 ou 1.
  4. Composé hétérocyclique condensé, sel, hydrate, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci tel que défini dans la revendication 2, dans lequel,
    le cycle hétérocyclique formé par R5, R6, avec l'atome d'azote auquel ils sont directement liés est un cycle hétéroalicyclique à 6 chaînons contenant de l'azote ; le cycle hétéroalicyclique à 6 chaînons contenant de l'azote est une pipéridine ou une pipérazidine.
  5. Composé hétérocyclique condensé, sel, hydrate, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci tel que défini dans la revendication 1, dans lequel
    la formule I est un composé sélectionné dans le groupe constitué de :
    Figure imgb0132
    Figure imgb0133
    Figure imgb0134
    Figure imgb0135
    Figure imgb0136
    Figure imgb0137
    Figure imgb0138
    Figure imgb0139
     et
    Figure imgb0140
  6. Procédé de préparation du composé hétérocyclique condensé, du sel, hydrate, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci tel que défini dans l'une quelconque des revendications 1 à 5, dans lequel
    la voie réactionnelle I comprend les étapes suivantes :
    Figure imgb0141
    la voie réactionnelle IV comprend les étapes suivantes :
    Figure imgb0142
     dans lequel,
    RX est
    Figure imgb0143
    Figure imgb0144
     ou -(CR8R9)mNR5R6, quand R2 est
    Figure imgb0145
    Figure imgb0146
    Figure imgb0147
     ou -O(CR8R9)mNR5R6 dans la formule I, la voie réactionnelle IV est utilisée pour la synthèse, quand R2 n'est pas
    Figure imgb0148
    Figure imgb0149
    Figure imgb0150
     ou -O(CR8R9)mNR5R6 dans la formule I, la voie réactionnelle I est utilisée pour la synthèse ; X1 est Cl, Br ou I.
  7. Composé tel que représenté ci-dessous :
    Figure imgb0151
  8. Composition pharmaceutique comprenant une dose thérapeutiquement efficace du composé hétérocyclique condensé, d'un sel, hydrate, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci tel que défini dans l'une quelconque des revendications 1 à 5, et un support pharmaceutiquement acceptable.
  9. Composé hétérocyclique condensé, sel, hydrate, solvate ou polymorphe pharmaceutiquement acceptable de celui-ci tel que défini dans l'une quelconque des revendications 1 à 5, ou la composition pharmaceutique telle que définie dans la revendication 8 pour une utilisation dans le traitement et/ou la prévention d'une maladie associée à une kinase, dans lequel :
    la « maladie associée à une kinase » est une maladie sélectionnée dans le groupe constitué d'un cancer, des maladies immunologiques, d'un dysfonctionnement métabolique et/ou endocrinien, d'une angiocardiopathie, des infections virales et d'une inflammation, et des maladies des nerfs, de préférence dans lequel la maladie immunologique est une maladie sélectionnée dans le groupe constitué de la polyarthrite rhumatoïde, du psoriasis, de la rectocolite hémorragique, de la maladie de Crohn et du lupus érythémateux disséminé ; l'angiocardiopathie est un trouble hématologique néoplasique ; l'infection virale et l'inflammation sont l'asthme et/ou la dermatite atopique.
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AU2014336775A1 (en) 2016-04-21
TWI631115B (zh) 2018-08-01
CN106831722A (zh) 2017-06-13
RU2663999C2 (ru) 2018-08-14
RU2016115934A (ru) 2017-11-20
CN104557872A (zh) 2015-04-29
JP2016533372A (ja) 2016-10-27
TW201518288A (zh) 2015-05-16
NZ718487A (en) 2020-01-31
CN104557872B (zh) 2017-05-24
HK1209738A1 (en) 2016-04-08
US9656996B2 (en) 2017-05-23
JP6139789B2 (ja) 2017-05-31
IL245112B (en) 2020-10-29
US20160244432A1 (en) 2016-08-25
EP3059238A1 (fr) 2016-08-24
CN106831722B (zh) 2019-08-30
SG11201602446VA (en) 2016-05-30
MX2016004964A (es) 2016-07-11
IL245112A0 (en) 2016-06-30
EP3059238A4 (fr) 2017-04-12
CA2926596A1 (fr) 2015-04-23
AU2014336775B2 (en) 2018-04-05
KR101982912B1 (ko) 2019-09-10
CN106831721B (zh) 2019-10-22
KR20160062170A (ko) 2016-06-01
CN106831721A (zh) 2017-06-13
WO2015055071A1 (fr) 2015-04-23

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